Benign prostatic hyperplasia (BPH) is the second leading cause of surgery in males in the United States. It has been estimated that 20% of all men who reach 80 years of age will require surgery alleviate urinary obstruction secondary to this pathology. This program project represents a multidisciplinary study in the areas of etiology and prevention, new therapeutic approaches and better definitions of the pathology and morbidity caused by BPH. Etiology and Prevention: Experiments are designed to test the effects of events occurring early that impact on the development of BPH later in life. It has been determined that canine BPH is characterized by a prostate gland that is inherently marked to abnormal growth. This growth appears to be an imbalance between cell replication and cell death, with both events being altered by estrogens and androgens. It appears that BPH may be a stem cell disease that is programmed by events occurring early in life because we have been able to alter the pathogenesis of the disease by removing the testes early in life and then maintaining normal levels of androgens and estrogens in the blood. This treatment prevents some dogs from developing the disease, while in others BPH pathogenesis proceeds as expected. We believe that this difference may involve a variation in the imprinting phenomenon that may be controlled by both endogenous estrogens and/or spurious estrogens arising from the diet. We propose to begin to sort out these factors and to determine their effects on various cell types within the prostate, to elucidate the molecular events that are imprinted early in life including tissue-specific gene expression, DNA methylation, cell turnover and the location of specific steroid receptors and growth factors within the prostate gland. Studies will be completed in rats and in dogs in a manner designed to control spurious estrogens arising from the diet; in dogs the effect of the in utero environment also will be examined. Therapeutic Studies: Differentiating agents will be tested for their ability to induce the prostate through its maturation block. Aromatase inhibitors will be tested under conditions where androgen stimulation of prostate growth is controlled. Pathology and Morbidity: A comparative study of the prostate is proposed including new models to study the effects of lower tract obstruction on the pathology of the bladder. All these programs are designed to contribute basic knowledge to our understanding the cause, effects and control of BPH.